U.S. Pat. No. 6,441,049 B2 disclsoes a method of treating nerodegenerative disorders via inhibition of amyloid beta peptide binding.
U.S. Pat. No. 6,255,490 B1 discloses 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands.
U.S. Pat. No. 6,060,473 discloses7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands.
U.S. Pat. No. 6,054,464 discloses azabicyclic esters of carbamic acids useful in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders, as well as intermediates and use of intermediates in synthesis.
U.S. Pat. No. 5,977,144 discloses compositions for benzylidene- and cinnamylidene-anabaseines and methods for using these compositions for treating conditions associated with defects or malfunctioning of nicotinic subtypes brain receptors. These compositions target the α7 receptor subtype with little or no activation of the α4β2 or other receptor subtypes.
U.S. Pat. No. 5,712,270 discloses a group of 2-aroylaminothiazole derivatives which bind to and stimulate central muscarinic acetylcholine receptors and are useful agents for treating symptoms of cognitive disorders, specifically the impaired memory associated with a decrease in the neurotransmitter, acetylcholine. Some of the compounds of this invention also bind to 5HT1A receptors and dopamine D2 receptors, making them useful as antipsychotic agents.
U.S. Pat. No. 5,624,941 discloses pyrazole derivatives useful in pharmaceuticals in which cannabis is known to be involved.
U.S. Pat. No. 5,561,149 discloses the use of a mono or bicyclic carbocyclic, or heterocyclic carboxylic, acid ester or amide or an imidazolyl carbazol in the manufacture of a medicament suitable for the treatment of stress-related psychiatric disorders, for increasing vigilance, for the treatment of rhinitis or serotonin-induced disorders and/or coadministration with another active agent to increase the bioavailability thereof, or for nasal administration.
U.S. Pat. No. 5,510,478 discloses a group of 2-aroylaminothiazole derivatives which bind to and stimulate central muscarinic acetylcholine receptors and are useful agents for treating symptoms of cognitive disorders, specifically the impaired memory associated with a decrease in the neurotransmitter, acetylcholine. Some of the compounds of this invention also bind to 5HT1A receptors and dopamine D2 receptors, making them useful as antipsychotic agents.
U.S. Pat. No. 5,364,863 discloses bicyclic carboxylic esters and amides, their pharmaceutical formulations, and a method for their use in treating migraine, emesis, gastrointestinal-disorders, schizophrenia, or anxiety in mammals.
U.S. Pat. No. 5,217,975 discloses azabicyclic compounds for treating dementia.
U.S. Pat. No. 5,106,843 discloses heterocyclic compounds useful as 5-HT3 antagonists.
U.S. Pat. No. 5,057,519 discloses 5-HT3 antagonists as being useful in reducing opiate tolerance.
U.S. Pat. No. 5,039,680 discloses 5-HT3 antagonists in preventing or reducing dependency on dependency-inducing agents.
U.S. Pat. No. 4,988,691 discloses isoxazole-containing compounds exhibiting anti-serotonin activity.
U.S. Pat. No. 4,921,982 discloses 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids which are useful as intermediates for 5-HT3 antagonists.
U.S. Pat. No. 4,863,919 discloses a method of enhancing memory or correcting memory deficiency with arylamido- (and arylthioamido-)azabicyclalkanes.
U.S. Pat. No. 4,835,162 discloses agonists and antagonists to nicotine as smoking deterrents.
U.S. Pat. No. 4,605,652 discloses a method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes, and the pharmaceutically acceptable acid addition salts, hydrates and alcoholates thereof.
U.S. patent application Ser. No. 2002/0016334 discloses a pharmaceutical composition for the treatment of attention deficit hyperactivity disorder.
WO 01/60821 discloses novel biarylcarboxamides.
WO 01/36417 A1 discloses novel N-azabicyclo-amide derivatives and use in therapy, especially in the treatment of prophylaxis of psychotic disorders and intellectual impairment disorders.
WO 01/29304 discloses quinuclidine acrylamides.
WO 00/73431 A2 discloses two binding assays to directly measure the affinity and selectivity of compounds at the α7 nAChR and the 5-HT3R. The combined use of these functional and binding assays may be used to identify compounds that are selective agonists of the α7 nAChR.
WO 98/54189 discloses spiro-quinuclidine derivatives, their preparation and use.
WO 97/30998 discloses azabicyclic esters of carbamic acids useful in therapy.
WO 95/01793 discloses 5-HT3 antagonists as topical medicaments for treatment of peripheral disorders associated with pain.
WO 92/15579 discloses multicyclic tertiary amine polyaromatic squalene synthase inhibitors and method of treatment for lowering serum cholesterol levels using the compounds.
WO 92/21339 discloses isoxazole and isothiazole compounds that enhance cognitive function.
JP 04-247081 discloses 5-membered heterocyclic acid amides.
In Bioorg. & Med. Chem. Lett. 11 (2001) 319-321, the 5-HT3 antagonist tropisetron (ICS 205-930) is discussed as a potent and selective α7 Nicotinic receptor partial agonist.
In Behavioral Brain Res., 113 (2000) 169-181, it is discussed that the brain α7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease using DMXBA which is known as GTS-21.
In J Med. Chem., 40 (1997), 4169-4194, neuronal nicotinic acetylcholine receptors are discussed as targets for drug discovery.
In Science, 279 (1998), 77-81, the broad-spectrum, non-opioid analgesic activity is discussed by selective modulation of neuronal nicotinic acetylcholine receptors.
Cell surface receptors are, in general, excellent and validated drug targets. nAChRs comprise a large family of ligand-gated ion channels that control neuronal activity and brain function. These receptors have a pentameric structure. In mammals, this gene family is composed of nine alpha and four beta subunits that co-assemble to form multiple subtypes of receptors that have a distinctive pharmacology. Acetylcholine is the endogenous regulator of all of the subtypes, while nicotine non-selectively activates all nAChRs.
The α7 nAChR is one receptor system that has proved to be a difficult target for testing. Native α7 nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar, J Neurochem., 1997, 68(5):2140-51). Another feature that makes functional assays of α7 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.
Recently, Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the α7 nAChR (Eisele et al., Nature, 366(6454), p 479-83, 1993), and the pore forming C-terminal domain of the 5-HT3 receptor expressed well in Xenopus oocytes while retaining nicotinic agonist sensitivity. Eisele et al. used the N-terminus of the avian (chick) form of the α7 nAChR receptor and the C-terminus of the mouse form of the 5-HT3 gene. However, under physiological conditions the α7 nAChR is a calcium channel while the 5-HT3R is a sodium and potassium channel. Indeed, Eisele et al. teaches that the chicken α7 nAChR/mouse 5-HT3R behaves quite differently than the native α7 nAChR with the pore element not conducting calcium but actually being blocked by calcium ions. WO 00/73431 A2 reports on assay conditions under which the 5-HT3R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor.